TY - JOUR
T1 - Intratumoral injection of clostridium novyi-NT spores in patients with treatment-refractory advanced solid tumors
AU - Janku, Filip
AU - Zhang, Halle Huihong
AU - Pezeshki, Abdulmohammad
AU - Goel, Sanjay
AU - Murthy, Ravi
AU - Wang-Gillam, Andrea
AU - Shepard, Dale R.
AU - Helgason, Thorunn
AU - Masters, Tyler
AU - Hong, David S.
AU - Piha-Paul, Sarina A.
AU - Karp, Daniel D.
AU - Klang, Mark
AU - Huang, Steven Y.
AU - Sakamuri, Divya
AU - Raina, Anjali
AU - Torrisi, Jean
AU - Solomon, Stephen B.
AU - Weissfeld, Alice
AU - Trevino, Ernest
AU - DeCrescenzo, Gary
AU - Collins, Amanda
AU - Miller, Maria
AU - Salstrom, Jennifer L.
AU - Korn, Ronald L.
AU - Zhang, Linping
AU - Saha, Saurabh
AU - Leontovich, Alexey A.
AU - Tung, David
AU - Kreider, Brent
AU - Varterasian, Mary
AU - Khazaie, Khashayarsha
AU - Gounder, Mrinal M.
N1 - Funding Information:
F. Janku reports other from Biomed Valley Discoveries during the conduct of the study; other from Novartis, Genentech, Astellas, Agios, Plexxikon, Piqur, Symphogen, Bristol-Myers Squibb, Asana, and Upsher-Smith Laboratories; personal fees and other from Deciphera and Cardiff Oncology; personal fees from Guardant Health, IFM Therapeutics, Synlogic, and Immunomet outside the submitted work. S. Goel reports other from Biomed Valley Discovery during the conduct of the study. D.S. Hong reports research/grant funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Numab, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics, and Verstatem; travel, accommodations, expenses from Bayer, LOXO, miRNA, Genmab, AACR, ASCO, and SITC; consulting or advisory role for Alpha Insights, Acuta, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Boxer Capital, COG, ECOR1, Expert Connect, Genentech, GLG, Group H, Guidepoint, H.C. Wainwright, Infinity, Janssen, Merrimack, Medscape, NTRK Connect, Numab, Pfizer, Prime Oncology, Seattle Genetics, SlingShot, Takeda, Trieza Therapeutics, and WebMD; and has other ownership interests for Molecular Match (advisor), OncoResponse (founder), and Presagia Inc (advisor). S.A. Piha-Paul reports other from Abbvie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Daichi Sanko, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Medimmmune, LLC, Medivation, Inc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, and NCI/NIH P30CA016672—core grant (CCSG shared resources) outside the submitted work. S.B. Solomon reports grants from Biomed Valley during the conduct of the study; grants from GE Healthcare and personal fees from XACT Robotics outside the submitted work. G.A. DeCrescenzo reports other from BioMed Valley Discoveries, Inc. during the conduct of the study. A. Collins reports other from BioMed Valley Discoveries, Inc. during the conduct of the study. M. Miller reports other from BioMed Valley Discoveries during the conduct of the study. J.L. Salstrom is employed by a contract research organization and has exposure to data from potentially competing clinical trials, but no specific conflicts were present during the conduct of this study. L. Zhang reports other from BioMed Valley Discoveries during the conduct of the study. S. Saha reports other from during the conduct of the study and outside the submitted work. D. Tung is an employee of Biomed-Valley Discoveries, and has nothing additional to disclose. B. Kreider is an employee of BioMed Valley Discoveries who sponsored and supported the Clinical Trial. M. Varterasian reports personal fees from BioMed Valley Discoveries, Inc. during the conduct of the study; personal fees from Takeda, UNUM Therapeutics, Boston Biomedical, Inc., Infinity Pharma, Molecular Templates, Synlogic Therapeutics, Bryologyx, and Skyline Biosciences outside the submitted work. K. Khazaie reports grants from Mayo Clinic during the conduct of the study. M.M. Gounder reports institutional research grant from BioMed Valley Discoveries, personal fees from Epizyme, Springworks, Karyopharm, Daiichi, Bayer, Amgen, Tracon, Flatiron, Medscape, Physicians Education Resource, Guidepoint, GLG and UpToDate; and grants from the National Cancer Institute, National Institutes
Funding Information:
The study was funded by BioMed Valley Discoveries Inc.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Purpose: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. Patients and Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 104 to 3 106 spores, 3þ3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose. Results: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n ¼ 2) and grade 4 gas gangrene (n ¼ 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n ¼ 1), limb abscess (n ¼ 1), soft-tissue infection (n ¼ 1), respiratory insufficiency (n ¼ 1), and rash (n ¼ 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. Conclusions: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.
AB - Purpose: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. Patients and Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 104 to 3 106 spores, 3þ3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose. Results: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n ¼ 2) and grade 4 gas gangrene (n ¼ 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n ¼ 1), limb abscess (n ¼ 1), soft-tissue infection (n ¼ 1), respiratory insufficiency (n ¼ 1), and rash (n ¼ 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. Conclusions: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.
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UR - http://www.scopus.com/inward/citedby.url?scp=85100334775&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-2065
DO - 10.1158/1078-0432.CCR-20-2065
M3 - Article
C2 - 33046513
AN - SCOPUS:85100334775
SN - 1078-0432
VL - 27
SP - 96
EP - 106
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -
